PROJECT SUMMARY/ABSTRACT Of the nearly 9 million new case of tuberculosis (TB) in 2011, it is estimated that 500,000 were multidrug-resistant (MDR), but less than 20% were started on MDR-TB treatment. The inability to make the diagnosis of MDR-TB in the ambulatory setting, limited bed capacity at specialized treatment centers, and resource-intensive, prolonged treatment courses of toxic medication regimens, contribute to the failure to initiate MDR-TB treatment which drives mortality and fuels community transmission. Fortunately rapid diagnostics like the Xpert MTB/RIF can now detect MDR-TB in the time of a single clinic visit, and large scale roll-out to ambulatory screening sites are underway (including at our study sites in Bangladesh and Tanzania). Yet the swell of new, largely ambulatory, patients will further create a treatment bottleneck unless governmental TB programs are massively expanded, or the duration of treatment regimens can be shortened and administered outside of the hospital. The latter is most immediately achievable. To do so, we propose an innovative approach to both minimize the necessity for prolonged hospitalization and to shorten the total treatment duration. We will test this approach by (1) employing a regimen of optimized pharmacokinetics based on local quantitative susceptible testing, (2) limiting the exposure to the most resource-intensive and toxic component of the multidrug regimen, the injectable aminoglycoside, and (3) applying the regimen to an ambulatory population with low bacterial burden. Thus, the proposed phase IIb non-inferiority trial, Reduced Injectable, Short-course for (E)Xpert MDR-TB (RISE trial), will randomize ambulatory patients newly diagnosed with MDR-TB by the Xpert MTB/RIF assay to the novel regimen (1 month injectable aminoglycoside, 12 months total treatment duration) or the current standard of care (6+ months injectable aminoglycoside, 20+ months total treatment duration) to compare rates of treatment success, and medication related adverse events. This proposal leverages strong collaboration with the University of Virginia and the clinical trials infrastructure of the Kilimanjaro Clinical Research Institute in Tanzania and the ICDDR,B in Bangladesh. The R34 will allow critical assessment of trial design, provide support for development of a complete study protocol, operations manual, and data management system, and securing of preliminary approvals.